Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer

  • Cancer Discov. 2025 Oct 15. doi: 10.1158/2159-8290.CD-25-0605.
Franziska Siegel  1 ,  Stephan Siegel  2 ,  Kristýna Kotýnková  3 ,  Gizem Karsli Uzunbas  3 ,  Daniel Korr  4 ,  Haruna Tomono  3 ,  Sawyer Andersen  3 ,  Daniel Denney  3 ,  Markus Berger  5 ,  Volker K Schulze  2 ,  Timothy A Lewis  6 ,  Bethany Kaplan  3 ,  Sven Golfier  4 ,  Jérémie Mortier  5 ,  Roman C Hillig  4 ,  Ulf Boemer  7 ,  Kirstin Petersen  5 ,  Knut Eis  5 ,  Sybil Williams  8 ,  Dominik Rüttinger  5 ,  Andrew D Cherniack  3 ,  Herbert H Loong  9 ,  Koichi Goto  10 ,  Paolo Grassi  11 ,  Matthew Meyerson  12 ,  Heidi Greulich  3
Affiliations
  • 1. Bayer AG, Germany.
  • 2. Bayer (Germany), Berlin, Germany.
  • 3. Broad Institute, Cambridge, MA, United States.
  • 4. Nuvisan ICB GmbH, Berlin, Germany.
  • 5. Bayer AG, Berlin, Germany.
  • 6. Broad Institute, Cambridge, United States.
  • 7. Nuvisan (Germany), Germany.
  • 8. Bayer HealthCare Pharmaceuticals, Cambridge, Massachusetts, United States.
  • 9. Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.
  • 10. National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
  • 11. Bayer (Italy), Milan, Italy.
  • 12. Dana-Farber Cancer Institute, Boston, MA, United States.
PMID: 41090369 DOI: 10.1158/2159-8290.CD-25-0605
Abstract

Exon 20 insertions of HER2, encoded by ERBB2, and Other activating HER2 mutations occur in 2-4% of lung adenocarcinomas, but there are only limited therapeutic options available for these patients. Sevabertinib (BAY 2927088) is a potent and reversible dual EGFR-HER2 inhibitor that is selective with respect to wild-type EGFR. Here, we report the preclinical activity of sevabertinib in lung Cancer models harboring alterations of HER2, including exon 20 insertions, point mutations, and amplification of wild-type ERBB2. We furthermore demonstrate the activity of sevabertinib in a Cancer cell line dependent on a fusion of NRG1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a Phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung Cancer.

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